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Abstract. It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless of O6-methylguanine-methyltransferase promoter methylation status. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma. The 32 enrolled patients were divided into two groups, KD or standard diet, with intranasal POH treatment (n=17 and n=15, respectively). The nutritional status and anthropometric parameters of the patients were measured. Patients that adhered to the KD maintained a strict dietary regimen, in addition to receiving 55 mg POH four times daily, in an uninterrupted administration schedule for three months. Neurological examination and magnetic resonance imaging analysis were used to monitor disease progression. A total of 9/17 patients in the KD group survived and maintained compliance with the KD. After three months of well-tolerated treatment, a partial response (PR) was observed for 77.8% (7/9) of the patients, stable disease (SD) in 11.1% (1/9) and 11.1% (1/9) presented with progressive disease (PD). Among the patients assigned to the standard diet group, the PR rate was 25% (2/8 patients), SD 25% (2/8) and PD 50% (4/8 patients). The patients assigned to the KD group presented with reduced serum lipid levels and decreased low-density lipoprotein cholesterol levels. These results are encouraging and suggest that KD associated with intranasal POH may represent a viable option as an adjunct therapy for recurrent GBM.

Intranasal administration of POH increased the overall survival of patients with recurrent GBM in comparison with historical untreated controls, but especially patients with secondary GBM and primary GBM with tumor localized in deep regions of the brain. The side effects of POH treatment were almost nonexistent, even in patients treated for over 4 years.

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Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal administration of cancer drugs has the potential to reach the brain via direct nose-to-brain transport, thereby circumventing the obstacle posed by the BBB. However, in the field of cancer therapy, there is a paucity of studies reporting positive results with this type of approach. A remarkable exception is the natural compound perillyl alcohol (POH). Its potent anticancer activity was convincingly established in preclinical studies, but it nonetheless failed in subsequent clinical trials, where it was given orally and displayed hard-to-tolerate gastrointestinal side effects. Intriguingly, when switched to intranasal delivery, POH yielded highly promising activity in recurrent glioma patients and was well tolerated. As of 2018, POH is the only intranasally delivered compound in the field of cancer therapy (outside of cancer pain) that has advanced to active clinical trials. In the following, we will introduce this compound, summarize its molecular mechanisms of action, and present the latest data on its clinical evaluation as an intranasally administered agent for glioma.

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The extracellular matrix (ECM) in the brain tissue is a complex network of glycoproteins and proteoglycans that fills the intercellular space serving as scaffolding to provide structural framework for the tissue and regulate the behavior of cells via specific receptors -integrins. There is enormous structural diversity among proteoglycans due to variation in the core protein, the number of glycosaminoglycans chains, the extent and position of sulfation. The lectican family of proteoglycans interacts with growth factors, hyaluronan and tenascin forming a complex structure that regulates neuronal plasticity and ion homeostasis around highly active neurons. In this review, we will discuss the latest insights into the roles of brain glycoproteins as modulators of cell adhesion, migration, neurite outgrowth and glial tumor invasion. Key words: glycoproteins, extracellular matrix, brain microenvironment, glioma. Cérebro doce cérebro: importância dos açúcares para o microambiente cerebral e o desenvolvimento tumoral RESUMOA matriz extracelular (ECM) no tecido cerebral é formada por uma rede complexa de glicoproteínas e proteoglicanas que preenchem o espaço intercelular participando como estrutura de sustentação do arcabouço tecidual regulando a função celular por interações com receptores específicos -as integrinas. Existe enorme diversidade estrutural entre as proteoglicanas, devido à variação na proteína central (core), à quantidade de cadeias de glicosaminoglicanas, ao grau e posição de grupamentos sulfato na molécula. As proteoglicanas lecticanas interagem com fatores de crescimento, com hialuronana e tenascina formando uma estrutura complexa regulando a homeostase de íons e a plasticidade neuronal. Neste artigo de revisão serão apresentados dados relevantes da literatura sobre o papel das glicoproteínas no microambiente do tecido cerebral, como moduladores da neuritogênese, da adesão, migração celular e invasividade de células tumorais de origem glial. Palavras-chave: glicoproteínas, matriz extracelular, microambiente cerebral, glioma. The brain presents restricted well-defined stromal space. A large proportion of the brain volume consists of space between neurons and astrocytic processes filled with extracellular matrix (ECM) components that influence neuronal communication and regulate plastic changes protecting neurons and synapses against damage. The brain ECM is unique in composition and organization as it contains relatively small amounts of fibrous proteins but high amounts of carbohydrates either bound to proteins forming proteoglycans (PG) or unbound in the form of hyaluronan which are abundant in the brain parenchyma. Conversely, the cerebral vascular basement membrane surrounding blood vessels contains type-IV and type-V-collagens, fibronectin, laminin, vitronectin and heparan-sulfate proteoglycans 1 .

The monoterpene perillyl alcohol (POH) is a drug used in the treatment of several malignant tumors, including gliomas. The present study defines a POH inhibitory effect on Na/K-ATPase activity from kidney and brain guinea pig extracts and from a human glioblastoma cell line. This inhibition showed a high degree of selectivity toward the kidney enzyme expressing, as do glioblastoma cells, the α(1) subunit. Kinetic studies with purified enzymes showed a noncompetitive POH inhibition profile to Na(+) and K(+) and an uncompetitive inhibition towards ATP. Furthermore, potassium activated p-nitrophenylphosfatase activity of these purified preparations was not inhibited by POH, suggesting that this drug, differently from the classical inhibitor ouabain, acted in the initial phase of the enzyme's catalytic cycle. We suggest that POH antitumor action could be linked to its Na/K-ATPase binding properties.